Molecules 2013, 18, 11586-11600; doi:10.3390/molecules180911586 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Plasticity of the Human Olfactory System: The Olfactory Bulb Caroline Huart 1,2*, Philippe Rombaux 1,2 and Thomas Hummel 3 1 Department of Otorhinolaryngology, Cliniques Universitaires Saint-Luc, Brussels 1200, Belgium 2 Institute of Neuroscience, Université catholique de Louvain, Brussels 1200, Belgium; E-Mail: [email protected] 3 Department of Otorhinolaryngology, Technical University Dresden Medical School, Dresden 01307, Germany; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +32-2-764-19-49; Fax: +32-2-764-89-35. Received: 15 August 2013; in revised form: 3 September 2013 / Accepted: 11 September 2013 / Published: 17 September 2013 Abstract: In the last years, an increasing interest has been paid to the olfactory system, particularly to its abilities of plasticity and its potential continuous neurogenesis throughout adult life. Although mechanisms underlying adult neurogenesis have been largely investigated in animals, to some degree they remain unclear in humans. Based on human research findings, the present review will focus on the olfactory bulb as an evidence of the astonishing plasticity of the human olfactory system. Keywords: olfaction; olfactory bulb; plasticity 1. Introduction Olfaction plays a major role in our interaction with the environment. The olfactory system not only acts for the detection of potential dangers in the environment, such as smoke, gas or dusts, but also it influences our nutrition, social behavior, and well-being. The olfactory bulb (OB) plays the central role in the processing of olfactory information. It is the only relay between periphery and the central nervous system; it also processes olfactory information. The OB volume varies as a function of olfactory sensitivity and is decreased in patients with olfactory disorders (i.e., post-infectious, post-traumatic, or sinunasal olfactory loss) [1–5]. But even Molecules 2013, 18 11587 more interestingly, the OB volume may increase during recovery from the olfactory disorder, highlighting its plasticity [6]. It has been hypothesized that this plasticity could be due to the particularity of the olfactory system that is continuous neurogenesis throughout adult life (e.g., [7]). Two major mechanisms of neurogenesis have been proposed–and they are still under discussion (e.g., [8,9]). The first one is the continuous renewal of olfactory receptor neurons (ORNs) from basal cells at the level of the olfactory neuroepithelium and the synaptogenesis that occurs between the axons of ORNs and mitral cells at the glomerular level. The second one is the continuous neurogenesis from the subventricular zone of the lateral ventricle, leading to the generation of neuroblasts that migrate along the rostral migratory stream and that will differentiate into interneurons inside the OB. For years adult neurogenesis has been a topic of high interest. If adult neurogenesis has been largely investigated in animals, only few studies have investigated the neurogenesis in humans. However, the animals and human olfactory system show noticeable differences and extrapolation of animal studies to humans might be too simplistic and misrepresent the reality. Focusing on human findings, the present review attempts to discuss the plasticity within the human OB. 2. Anatomy and Physiology of the OB The OB is ovoid in shape and located in the anterior cranial fossa, above the cribriform plate of the ethmoid bone, under the frontal lobe (Figure 1). It receives axons from the olfactory receptor neurons (ORNs), which pass through the cribriform plate of the ethmoid bone; converge into the olfactory nerves, surrounded by glial cells (called olfactory ensheating cells) and project directly to the ipsilateral OB. Figure 1. Coronal T2-weighted images of the olfactory bulbs (OBs) in normal subject (A) and in patients suffering from post-infectious (B) and post-traumatic (C) olfactory loss. The OBs (white arrow) are located above the cribriform plate of the ethmoid bone, under the frontal lobes. The olfactory sulcus is indicated by a black arrow. The OB is decreased in patients suffering from post-infectious olfactory loss (B) as well as in patients suffering from post-traumatic olfactory loss (C). Moreover, in the later OB is fragmented and basifrontal contusions may be observed (asterisk). ORNs are bipolar cells, with their body located in the olfactory neuroepithelium and their dendritic extensions directed toward the olfactory cleft, carrying on their surface several cilia surrounded by Molecules 2013, 18 11588 olfactory mucus. Olfactory neuroepithelium is special in the sense that it is continuously regenerated throughout adulthood due to basal cell. Odorants reaching the olfactory cleft are probably carried through the mucus layer by olfactory binding proteins; and bind to olfactory receptors located at the ORNs’ cilia. In 1991, Axel and Buck [10] discovered a family of approximately 1,000 genes that encode for an equivalent number of olfactory receptors, corresponding to the largest family of genes in the mammalian genome [11], highlighting their important role in physiology. In the majority of mammals most of these genes are functional, but in primates the number of functional genes decreases and is only about 350 in humans [12]. Axel and Buck found that each ORN possesses only one type of odorant receptor and each receptor is specialized for a small number of odors. Hence, a given odorant will bind a typical pattern of olfactory receptors. In the OB, ORNs axons ramify and synapse with second order neurons (named mitral cells) into spherical structures known as glomeruli. Each glomerulus collects axons of ORNs that express the same receptor protein [13]. Glomeruli are major structures within the OB and can be considered to be the first olfactory structure, relaying directly the peripheral olfactory information to the central nervous system. The OB has a laminar organization arranged in circular layers. It encompasses six different layers, anatomically defined on the basis of cell type and composition: (1) the external or olfactory nerve layer is made up of axons of the incoming ORNs; (2) the glomerular layer is composed by glomeruli wherein axons of ORNs synapse with dendrites of mitral cells, periglomerular and tufted cells; (3) the external plexiform layer consists mainly of dendrites of mitral and tufted cells. Indeed, mitral and tufted cell extend secondary dendrites into this layer, where they synapse with local interneurons (juxtaglomerular, periglomerular and granule cells) (4) the mitral cells layer contains cell bodies of mitral cells (second order olfactory neurons); (5) the internal plexiform layer; and (6) the granule cell layer contains soma of the granule cells, which are GABAergic cells and represent the most numerous cells in the OB. Axons of the mitral cells and tufted cells coalesce to form the olfactory tract, located at the base of the forebrain. The olfactory tract conveys olfactory information to a wide number of brain regions within the frontal lobe and the dorsomedial surface of the temporal lobe, often referred to as primary olfactory cortex. This centripetal information then projects to the primary olfactory cortex (Figure 2). Glutamate is the principal neurotransmitter of the ORNs, mitral and tufted cells. Dopamine and GABA receptors are present on the receptor cells, allowing presynaptic modulation of the glutamate output by the interneurons [14,15]. However, it is important to note that numerous neurotransmitters are involved in bulbar cell interactions at the level of the glomerulus and within the external plexiform layer (for a review, see [16]). OB also receives centrifugal information, from higher structures of the brain (Figure 3). Centrifugal fibers, with GABA and acetylcholine as principal neurotransmitters, are essential to modulate the activity of the OB. Cholinergic fibers enter the bulb from the ispilateral nucleus of the horizontal limb of the diagonal band [17,18]. Centrifugal serotoninergic innervation from the dorsal and medial raphe nuclei, noradrenergic innervation from the locus coeruleus and glutamatergic innervation form the anterior olfactory nucleus are also present (for a review, see [16]). Interestingly, it has been demonstrated Molecules 2013, 18 11589 that the centrifugal projections from noradrenergic neurons located in the locus coeruleus is critical in early olfactory preferences learning, both in rodents [19,20] and humans [21,22]. In animals, it has been demonstrated that centrifugal fibers contribute to the context-dependent modulation of the OB activity and affect olfactory learning, memory, attention and odor-reward association (for a review see [23]). Figure 2. Centripetal (A) and centrifugal (B) information from and to the olfactory bulb. (A): Odorants reaching the olfactory cleft stimulate the olfactory receptor neurons (ORNs) located in the olfactory neuroepithelium. Axons of ORNs synapse with second order neurons at the level of the olfactory bulb (OB), and ORNs carrying the same odorant receptor project to the same glomeruli. The olfactory information is then transmitted to the primary olfactory cortex (POC) (composed by piriform cortex, entorhinal cortex, periamygdaloid cortex, anterior olfactory nucleus, olfactory tubercle). Primary olfactory cortex then projects, among